Process for preparing monoalkylaminoalkyl alkoxyaminobenzoates



7 PROCESS FOR PREPARING MONOALKYLAMINO- ALKYL ALKOXYAMINOBENZOATES Morri's Freifelder, Waukegan, 11]., assignor' to \bbott Laboratories, North Chicago, ]]l., a corporation of Illinois.

' No Drawing. Appli'cafion March 7, 1955 SeriaLNo. 492,768

Claims. (Cl. 260-472) This invention relatesto the preparation of monoalkylaminoalkyl esters'and: to. theester prepared by. the improved process.

In the preparation of mono-N-substituted aminoalkyl esters, such as the benzoates or substituted benzoates, by

reactinga mono-N-substituted aminoalkanol .with' an acyl-halide, such as benzoyl halides or substituted benzoyl tionof the-undesirable amides or etfect arearrangement of the amide to the ester in order to insure substantial yields-of the mono-N-substituted esters. In many instances, however, despite, the foregoing procedure, the amide'is formed'asthepredominant reactionproduct instead of the desiredester.

It is therefore an object'of'the present invention to provide-an improved method of" preparing monoalky-laminoalkyl esters withoutproducing substantial amounts of'the corresponding amide. 7

his another object of'the invention to provide animprovedmethod of preparing monalkylaminoalkyl' benzoates and monoalkylaminoalkyl substituted benzoates.

Other objects of the'invention will be apparent from the following detaileddescription and claims.

It has been found that monoalkylaminoalkyl esters in highly purified form substantially free of the corresponding amide products can be prepared in an economical manner by introducing a hydrogenolyzable' groupinto a monoalkylaminoalkanol on the nitrogen atom thereof, such as benzylating the said aminoalkanol, and thereafter reacting the thus substituted aminoalkanol with the-desired'acylating agent, such as benzoyl chloride. The fore going reaction product is then subjected to a reducing atmosphere. in whichthe said benzyl or other hydrogenolyzable group is removed from the nitrogen atom of the amino group andreplaced by hydrogento form adesired mono substituted alkylaminoalkyl ester. Among the hydrogenolyzable groups which have been found highly satisfactory in the present invention are the benzyl-group and carbobenzoxygroup although other groups. which are alkanol with a hydrogenolyzable; group: Which-.pmteetS United States PatentO 3 cc 2,828,329 Patented lVlar. 25 l95 8 theaaminogroup when the said alkanol is reacted with the. desired acyl halide tozform an ester. Itis'alsowithin the scope of the present invention,fhowever;. to react an; aminoalkanol with benzaldehydeor a. substituted benzaldehyd'e-to form an N-benzylamin'oalkanol anditherelafter alkylating the. saidtbenzylaminoalkanol to introduce therein the desired. monoalkylisubstituent in'; the: usual manner. In another procedure for preparation of benzylalkylaminoalkanols, benzylalkylamine compounds are reacted with alkylene oxides such as ethylene oxide, propylens oxide. and. the like to form benzylalkylaminoethanol,

benzylalkylaminoisopropanolE The aminoalkanol can also be provided with other hydrogenolyzable groups, such as benzhydryl, aor fi-menaphthyl, nuclear substituted carbobenzoxy such as p-bromcarbobenzoxy, carbo-allyloxy, and carbobenzoxy, as by reactin gthe aminoalkanol or N-monoalkylaminoalkanol with carbobenzoxy chloride In. ,the-: following; specific. examples. are showni several specific embodiments aofithe. present inventionbut-it should be. understood: thatthexinvention is. not to be limited to th'especific reactions disclosed nor; to-the; precise proportions. or; conditions :set; forth "in: they severali specific: examples,,sinee; the;exarnples;are:given:only fonthe purpose of illustrating the principle of the present; invention.-.

EXAMPLE I fi -p pylaminmethyl 4-methoxyb m i v ydrochloride.

(a) Z-(benzyl-n-propylamino)ethanol:- To- 75.5 g. 2-

'solution is refluxed for ZOminutes and, concentrated 11nmethanol is=added 5 8 g, propionaldeliyde-(lpomole The der reducedpressure to removevolatil'e materials. .Tliereafter 50 cc. methanol is addedtothe residue and the solution is hydrogenated undera pressure of 50 pounds per square i'nch'in the presence of platinum oxide; Upon'the completion of" the reduction, thereaction mixture-is filtered and the product, 2-(benzyl n-propylamino)ethanol,

is distilled at a temperature of 155-165 C. under? a pressure of 22 mm. and exhibits -a refractive index of r1 1151 10. Upon-analysis-the-said aminoethanol product is found to contain 74.90%: C, 9.84% H, and 6.98% N, as compared with theoretical values. of 74. 5,7% C,

b 2-(benZyl-n=propylamino) ethyl 4-methoxybenzoate hydrochloride: 2-(benzyl-n-propylamino)ethanol (29.5 g.) prepared in the. foregoingmanner is'dissolvedin 50 cc. of benzol, heated and stirred for a period of 30 minutes with 25.6 g. of anisoyl chloride dissolved in cc. of benzol. The mixture is then stirred and refluxed for four: hours. and allowed to stand-approximately 12 hours. The: reaction mixture is heated to removerthe sol- -vent. from thebreactioni mixture and a? non-crystalline hydrogenated under a pressure of 50 pounds per square inchinithe presence of 5.-O g. of 5'%' palladium-on'charcoal untibredzuctibn is complete, usuallyrequiringseveral homjssunderttheforegoingconditions. Thereafter water V is added to the reduction mixture to dissolve the product which comprises the hydrochloride salt of 2-(n-propylamino)ethyl 4-methoxybenzoate. Theproduct is filtered and concentrated under'r educed pressure and thereafter purified by dissolving in isopropyl alcohol and adding dryether to precipitate the purified Z-(n-propylamino) ethyl 4-methoxybenzoate hydrochloride which has a melting point of 148.5" C. On chemical analysis the'product is found to contain 56.90% C, 7.27% H, and 5.20% N, as compared with theoretical values of 57.01% C, 7.36% -H, and 5.11% N.

EXAMPLE H 2-(n-ptopylomino)ethyl 3-amino-4-n-butoxybenaoat e .hy-

drochloride (a) .Z-(benzyl-n-propylamino)ethyl 3-nitro-4-n-butoxybenzoate hydrochloride: 2-(benzyl-n-propylamino) ethanol -(0.1 mole), prepared as in Example 1(a), is dissolved in benzoland thereafter refluxed with stirring with 0.1 mole :of .3 nitro-4-n-butoxybenzoyl chloride for about three the solution is hydrogenated under a pressure of 32 pounds per square inch in the presence of 3.0 g. of 5% palladium on charcoal. with benzol and thereafter made alkaline with sodium hydroxide solution; The solution is then extracted with benzol and dried over magnesium sulfate. After filtering the solution, about 0.056 mole of alcoholic hydrochloric acid is added thereto and it is allowed to stand until precipitation is 'complete. The precipitate is filtered, washed with dry ether and dried thoroughly. The product, 2-(n-propylamino)ethyl 3-amino-4-n-butoxybenzoate hydrochloride, upon recrystallizationfrom ethyl alcohol and thorough drying, has a melting point of 141-l42 C. 'On chemical analysis the said product is found to contain 57.67% C, 7.90% H, and 8.01% N, as compared with theoretical values of 58.08% C, 8.22% H, and 8.47% N.

7 EXAMPLE III '2 (cyclohexylamino)ethyl 3 amino -4 n butoxybenzoate hydrochloride I i (a) 2-(cyclohexylbenzylamino)ethanol is prepared by .reacting 2-(benzylarnino)e'thanol with cyclohexanone and thereafter subjecting the reaction product to hydrogenationin accordance with Example I(a). The product is found to have a boiling point of 207 C. at a pressure of .22 mm. and has a refractive index of 11, 1.5287. On

chemical analysis the said product is found to contain 77.34% C, 10.01% H, and 5.99% N, as compared with theoreticalvalues of 77.20% C, 9.93% H, and 6.00% N.

The mixture is filtered, the filtrate treated (b) 2 (benzylcyclohexylamino)ethyl 3 nitro 4 nbutoxybenzoate hydrochloride is prepared by reacting 3- to give a product having a melting point of -409 C. On chemical analysis the said product is found to contain 5.63% N, as compared with a theoretical value of 5.85% N.

(c) 2 (cyclohexylamino)ethyl 3 amino 4 nbutoxybenzoate dihydrochloride is obtained by catalytically reducing the 3-nitro-4-n-butoxybenzoate product 'of Example III in the same manner as described in Example II. The said amino product melts at 211212.5 C. with decomposition. On chemical analysis the said product is found to contain 56.26% C, 7.71% H, and 6.88% N, as compared with theoretical values of 56.01% C, 7.92% H, and 6.88% N. 0

EXAMPLE IV 1- (methylamino -2-prop vl 3-anzino-4-n butoxybenzoate hydrochloride n-mnto o-'-odH-oH,Nnon..Ho1

NH: 1 V

(a) ll-(benz'ylmethylamino)-2-propanol is prepared by reacting l-(benz'ylamino)-2-propanol with formaldehyde and subjecting the reaction product tofhydrogenation as in Example 1(a). 'The product has a boiling point of -127-128-C. at a pressure of 13 mm. and has a refractive index of 11 1.5087. On chemical analysis the product isfound to contain 73.80% C, 9.60% H, and 7.88% N, as compared with theoretical values of 73.70% C, 9.56% H, and 7.81% N.

(b) l-(benzylmethylamino) 2 propyl 3-nitro-4-n-butoxybenzoate hydrochloride is prepared as in Example ll(a) by reacting .3 nitro-4-n-butoxybenzoyl chloride in .benzol with .l-(benzylmethylamino)-2-propanol and is found to have a-meltingpoint. of 78-83 C. On chemij calanalysis the product is found to contain 6.23% N as comparedwith a theoretical value of 6.41% N,

:I" (c) 'The product 1-(methylamino) -2-propyl 3-amino- 4-n-butoxybenzoate monohydro chloride is prepared as in Example He) by subjecting the 1-(benzylmethylamino)- 2-propyl 3-nitro4-n-butoxybenzoate hydrochloride to hydr'ogenation to give the product having a melting point of l38-l40 C. On chemical analysis the product is found to contain 56.91%C, 7.78% H, and 8.99% N, as compared with theoretic al values of 56.86% -C, 7.95% H,and 8.84% N. I 7 i EXAMPLE v 3-(methylami no')- 1 propyl 3-amino-4-n butoxybenzoate hydrochloride 7 I .n-mmofQiaw-omorncrn-NH-omnoi -(a) 3-(benzylmethylamiuo)-1-propanol"is prepared as 'in Example I by reacting 3-(benzylamino)propanol with formaldehyde and reducing thelreaction product in a "hydrogen atmosphere. The'product has a boiling point of l43147 C. at 'apressure of 11 mm. and a refractive index of 11 1.5216; fOn chemical analysis the'product 'is found to contain 73 .96% C, 9.26% H, and 7.67% N, as compared with theoretical values of 73.70% C, 9.56%

H, 'and 7.8l% N. I

(b) 3-(benzylmefl1ylamino) 1 propyl 3-nitro-4-n-butoxybenzoatehydrochloride is prepared as in Example II(a) by reacting 3-nitro-4-n-butoxybenzoylchloride with 3-(benzylmethylamino)1rpropanol to give a product having a melting point of 119-123 C. On chemical analysis'the product isfound to contain 60.69% C, 6.45% H, and 6.37% N, as compared with theoretical values of '60.50% C, 6.6 9% H, and 6.41% N. a

'benzoate hydrochloride is obtained'by dissolving 13.5 g. (0'.03 mole) of 3:(benzylmethylamino)-1propyl 3'-nitIo-4- on charcoal;

.n-butoxybenzoate hydrochloride in;75..cc. of...water and 15"cc. of alcohol'and'subjecting the solution-to hy dro-. genation under a pressure .of 30 pounds per square .inch

.in the presence of l:5'.g. of' 5%" palladium on charcoal.

EXAMPLE 'VI r 3-(cyclohexylamino)propyl 3-'amina'-4= n-butoxybenzqate dihydrochloride;

(a) 3-(cyclohexylcarbobenzoxyamino)propanol is prepared by reacting 31.4- g.,(0.2 mole) of 3-(cyclohexylamino) propanoldissolvedin 500cc. of benzol and 50 cc. of-dryether and 20.2 g.- (0.2rriole) f trietlztylami-m? with 34.1 g. (0.2 mole) of carbobenzoxy chloride which is added in small portions. Triethylamine hydrochloride begins to; precipitate immediately. 'The .mixture is*= warmed on a steam bath for several hours and filtered. After removing the solvent the residue comprising 3- (cyclohexylcarbobenzoxyamino)propanol' distills at a temperature of. 200=-20.7 C. at-iahpressure :of-6-7 mm. and has. a refractive index of u i-51524.3. analysis the. product is. found to: contain.'70;08.%.' C, 8.80%. H; and 5.06%.;N-,.as compared.with.theoretical valuesrof 70.06% C, 8:65.% H, and 4.8.1%'.;N;.

- 4+n=butoxybenzoate hydrochloride-is .preparedzbyreacting benzoylichloride iastin Example'l.

(c) 3-(cyclohexylamino)propyl 3-amino-4=n-'butoxybenzoate. dihydrochlorideris obtained :by hydrogenating a solution of 10.2. g. (0.02 mole.) of 3-(carbbben-zoxycyclohexylamino propyl 3-nitro-4-n-hutoxybenzoate in :100 cc.

of ethyl-alcohol lathe-presence 01: 1.0 g. of 5 ipalladium After. reduction is. .completexthe solution 'is filtered and 0.02 .moleof alcoholic hydrochloric acid is added and the solution concentrateddo. drynessunder reduced i pressure; The. residue is. treated with. acetone andfiltered to yield the.dihydrochloride.salt 'having a melting. .point of .216 C.v with decomposition: On chemical .analysis the said-salt is found to contain-57.40% C, 7.97% H, and 6.78% N,Las:compared with theoretical valuesofl57.69%lC, 7.91%.:H, and 6.66% N.

EXAMPLE VII 1 (methylamino -2.-propyl. 4.-amin0benz0ate: dihydrochloride 'hemih'ydrate;

O CHa (a). 1-(benzylmethylamino)-2-propyl 4 .nitrobenzoate hydrochloride is prepared by reacting 4-nitrobenzoyl chloride and l-(benzylinethylamino)-2 propanol as 'preparedin Example IV(a) according to the procedure benzoate dihydrochloride. is prepared by. reducing thesi- (benzylmethyl-amino)+2propy1 4-.nitrobenzoate: hydrochloride in alcohol withpalladium on charcoal as heretofore described. On chemical analysis the hemi-hydrate of the said dihydrochloride is found to contain 45.85

On. chemical 6 C, 6.59.% H, and, 9.82% N, as. compared with theoretical values,of'45.'52%" C, 6.60% H, and 9.64% N.

EXAMPLE VIII '5 2-?(n-but,ylamino)ethyl' 4-amin0benzoate hydrochloride (a) 2!.(benzyl-nbutylamino)ethylv 4-nitrobenzoate. hydrochloride, isprepared ,by, reacting 4-nitrobenzoyl chloride and 2-(bcnzyl-n-butylamino)ethanol according to theprocedure .in Example II(a).

(b) The a product. 2.-(n-butylamino)ethyl- 4-aminobenzoate. hydrochloride isprepared by hydrogenating Z-(benzyl-n-butylamino)ethyl 4-nitrobenzoate hydrochloride according to the procedure described in Example VlI(b)' to produce the said salt having a melting point of 140-14l C.,...which' -.on-. chemical. analysis is found. to contain 57.08% C, 7.94% H, and 10.27% N, as compared with theoretical values of 57.22% C, 7.76% H, and 10.27% N.

. v EXAMPLE IX I 2-(ethylamino)ethyl 3-amino 4-n-butoxybenzoate hydrochloride n-otmo -O-CHzOHzNHOzlEl .-H-Cl NH: (z'z)l 2 (benzylethylamino)ethanol is prepared -by.reacting-Q-(Bthylamino) ethanol with beuzaldehyde and hydrogenating-accordingto the procedure described in Example 1(a), said ethanol product distilling at a temperature-of 148-l56 C.' at-a pressure of 22 mm. and having a refractive index ofn LSZOO. On chemical analysisthe said product is-found to contain 73.66%- C, 9.32%-H, and -7'.72 N, ascompared with theoretical values of "73.70%

C, 9.56% H, and 7.81% N.

(b) 2-(benzylethylamino)ethyl- 3-nitro-4-n-butoxyben- 40 zoate. hydrochloride. is preparedzby'reacting 2:(benzylethylamino) ethanol with; 3-nitro-4-n-butoxybenzoyl chloride as in Example 1I(a) and has a melting point of 139-141 C. On chemical analysis-thesaid hydrochloride is foundto contain 60.69% C, 6.68% .Hyand 6.23% N, as compared with theoretical values of 60.50% C, 6.69% H, and 6.41% N.

(c) 2-(ethylarnino)ethyl' 3-arnino-4-nebutoxybenzoate hydrochloride is prepared by subjecting 2 (benzylethylamino ethyl 3 nitro-4-n-butoxybenzoate hydrochloride. to hydrogenationin accordance with theprocedure-described in..Ex,ample VII(c). The said amino. product has .a melting: point of' 128-129 C.v On chemical analysis the saidlproductris found to,contain 57.10%' C,1'8.03% H,

and; 8;86% N, as, compared with. theoretical. values, of .56.86% C, 7.95%.H', and.8.8j4%, Na

EXAMPLE X 2- (isopropylamino) ethyl 3-amina-4-nbutoxybenzoate hydrochloride 0 0H,. ll

n-C4Ha0 c-o-omonmrtcQ .1101

CH3- NH: (a) 2=.(benzylisopropylamino)ethanoL is prepared'by .65 reductive alkylationof,2-(isopropylamino)ethanol with benzaldehyde in accordance with the proceduredescribed heretofore and has aboilingpointof 142.5-143" C., at'a pressure of 22 mm. and a refractive index of n 1.5110. Orr-chemical, analysis the said aminoethanol;productis found to contain 74.63% 'C,.10.03% H, and 7.29% N, as compared with theoretical values of 74.57% C, 9.91% H, and 7.2 5% N. V

(b 2 (benzylisopropylamino) ethyl;'3 -nitro-4-n-butoxybenzoate hydrochloride is preparedby reacting 3-nitro- 4-n-butoxybenzoyl chloride with 2-(benzylisopropylamino)ethanol in accordance with the procedure described in'ExampleIKb), and has a'inelting' point of 128130 C. The said hydrochloride salt on chemical analysis is found to contain 60.20% C, 6.89% H, and 6.24% N, as compared with theoretical values of 60.47% c, 6.93% H, and 6.21% N. p

(c) 2-(isopropylamino)ethyl' 3-amino-4-n-butoxybenzoate hydrochloride is .preparedby'subjecting 2 -(benzyl- 'isopropylamino)ethyl 3 nitro-4n-butoxybenzoate .hydro- V chloride to hydrogenation in the presence 'of'palladi'um on carbon in the manner describedin Example VII. 7 The reaction product melts at 143-144C..and onchemical analysis is found to contain 58.19%" C, 8.12% H, and 8.58% N, as compared with theoretical 'C,.8.23% H, and 8.47%N.

. E XAMPLE i Z-(n-butylamino) ethyl 3-amino-4-n butojrybenzoate ih'ydrochloride 1 values of 58.08%

C. On chemical analysis the said product is found to contain 59.12% C, 8.69% H, and 8.12% N, as compared with theoretical values of 59.20% C, 8.47% H, and 8.12% N.

EXAMPLE XII Z-(n-propylamino) -butyl 3-amifio-4-n-butoxybenzoate dihydrochloride (a) 2-(benzyl-n-propylamino)-1-butanol is prepared by reductive alkylation of 2-(benzylamino)-1-butanol with propionaldehyde in accordance with the herein described procedure. The product boils at 162-16-7 C. at a pressure of 11 mm. and has a refractive index of n 1.5052.

On chemical analysis the product is found to contain 76.26% C, 10.39% H, and 6.53% N, as compared with theoretical values of 75.97% C, 10.47% H, and 6.33% N.

(b) 2-(benzyl-n-propylamino)-1-butyl 3-nitro-4-n-butoxybenzoate hydrochloride is prepared from the product of Example XII(a) in accordance with the previously described procedure and is obtained as a viscous oil.

(c) 2-(n-propylamino)-1-butyl -3-amino-4 n butoxybenzoate dihydrochloride is obtained in 63% yield by catalytic reduction of the product of Example XII (b) in accordance with the herein described procedure. The said dihydrochloride salt melts at 206-208 C. with decomposition. On chemical analysis the product is found to contain 54.63% C, 8.15% H, and 6.88% N, as compared with theoretical values of 54.66% C, 8.16% H, and

EXAMPLE XIII I-(n-propylamino) -2-pr0pyl 3-amino-4 r -butoxybenzoate dihydrochloride NH: 7 i I (a)' 1-(benzyl-n-propylamino)-2-propano1 is prepared by reductive 'alkyl'ation' of -1-(benzylamino)-2-propano1 with,propionaldehy'de. in accordance with the herein described procedure. -'The product boils at 141'143 C. at 'a pressureof 11.1mm.- andle'xhibits'a refractive index of n 5 1.5010."f On -chemical.analysis theproduct is found to contain 75.12%C, 10.17% H, and 6.62% N, as compared with theoretical values of 75.31% C, 10.21% H, and6.76%".N. f "('b) 1 (benzyl In propylamino) 2 propyl 3 5 nitro- 4-n-butoxybenzoate hydrochloride is'isolated as a thick viscous oil from the reaction of 3-nitro-4-n-butoxybenzo ,'l chloride with the product of Example X11101 (c) l-(n-propylamino)-2 propyl 3-amino-4-n-butoxy benzoate dihydrochloride is obtained by catalytic reduction of the product of Example XIII(b:);--The said dihydrochloride s'alt, after extensive drying, melts at 145-146 C. On chemical analysis the productis found to contain 53.58% C, 7.91% H, and 7.12% N, as compared with theoretical values of 53.53% C, 7.89% H, and 7.35% N.

i i EXAMPLE XIV Z-(isobutylamino) e'thyl 3-dmin0-4-n-but0rybenz0ate hydrochloride -o I on, n-c.u.o+ eoomomivncInch .HCl

, v i v CH3. V

' (a) 2-(benzylisobutylamino)ethanol is prepared by adding 15 cc. (0.3 mole) ethylene oxide to 49 g. (0.3 mole) N-benzylisobutylamine in a'well cooled stainless steel bomb. After sealing, the bomb is heated for about five hours. at -100" C. After distillation a product boiling at l63-170C.' under '21 mm. pressure and having a refractive index ofn 1.5034, is obtained. On chemical analysis the product is found to contain 75.46% C, 10.38%" H, 6.66%' N, and 7.84% O,'as compared with theoretical values of 75.31%tC, 10.21% H, 6.76% N, and 7.72% O. i c

(b) 2 '(benzylisobutylamino)ethyl 3 nitro 4 n butoxybenzoate hydrochloride is prepared by reacting 38.0 g. (0.183 mole) of the compound produced in Example XIV('a) in the herein disclosed manner with 0.183 mole'of 3-nitro-4-n-butoxybenzoyl chloride in benzol. The product'is a thick, viscous mass which is used as such for hydrogenation.

(c) 2-(isobutylamino)ethyl 3-amino-4-n-butoxybenzoatehydrochloride is prepared by catalytic reduction of an alcoholic solution of the. nitro ester hydrochloride as produced in' Example IV(b) After reduction is complete, the alcoholic filtrate is added to anhydrous ether and after precipitation-is complete, the mixture is filtered and washed with ether. A product melting at -97 C. is obtained. On chemical analysis the product is found to contain 58.96% C,8.60% H, and 7.93% N, as compared with theoretical valuesv of 59.20% C, 8.47% H, and 8.12% 'N.

It will be evident from the foregoing specific examples that the present invention provides an efficient and convenientprocess for the preparation of monoalkylaminoalkyl esters in a highly purified form and is particularly applicableto the preparation of amino benzoates and lower alkoxy substituted amino benzoates having the general formula:

mN V

wherein R is a lower alkyl group, R is a bivalent lower hydrocarbonradical, and R" is a lower alkyl group by reactingan alkanol having the general formula:

where R and R" have the above defined values and A isra, hydrogenolyzable group selected from. the group consisting of; benzyli benzliydryl,v u-menaphthyl .B-menaphthyl, carbobenzoxy, carborally loxy, and. halocarbobenzoxy, with1a benzoic,acid-acylatingagent having, the generalyformula:

B o. i

thereafter'subje'cting the said ester to a hydrogen reducing atmosphere to remove the said hydrogenolyzable group, and recovering the said monoalkylaminoalkyl ester compound as the salt or base uncontaminated by amide products.

The monoalkylaminoalkyl ester products having the latter general structure and particularly their water soluble non-toxic salts, such as the hydrochloride, the hydrobromide, the sulfate, and the nitrate, exhibit marked local anesthetic properties.

The esters of the present invention can, of course, also be prepared by using in the foregoing general reaction as the acylating agent a lower alkoxy ester of the desirably substituted benzoic acid and effecting an ester interchange in the usual manner in the presence of an alkaline catalyst, such as sodium ethoxide.

It should be readily understood that the herein disclosed process is also useful for the preparation of other monoalkylaminoalkyl esters former by reacting an aminoalkanol with an acylating agent which forms unsubstituted benzoates, aminobenzoates, lower alkyl substituted benzoates, and halogen substituted benzoates or similar esters wherein the ester compound does not possess substituents which are adversely affected by the reducing atmosphere used to remove the hydrogenolyzable group from the nitrogen atom of the alkylaminoalkyl group.

Others may readily adapt the invention for use under various conditions of service, by employing one or more of the novel features disclosed or equivalents thereof. As at present advised with respect to the apparent scope of my invention, I desire to claim the following subject matter.

I claim: 7 l. A process of preparing a compound selected from the group consisting of compounds having the general formula wherein R and R" have the above-defined values and Avis. a hydrogenolyzable group selected from; the.group consisting, of benzyl, benzhydryl, urmenaphthyl fl-menaphthyl, carbobenzoxy,' carbofallyloxy, and halocarbolbenzoxyrreactingthe said.aminoalkanol with a benzoic acid acylating agent having the general formula:

iwlierein is. ..a,.lower '.alkyl group, isselectedfrom the group consisting of Ithenitro and the. amino. groups, and :Xfisahalogenatom tolforman ester. having; the generaljormulat'. U

no A:

values, thereafter subjectingdhesaidsester to. a hydrogen reducing, atmosphere. to.-remove:.the said. hydrogenolyzable groupfand recovering the monoalkylaminoalkyl ester compound uncontaminated by amide products.

2. A process substantially as in claim 1 wherein the said aminoalkanol is prepared by reacting a secondary aminoalkanol having the general formula:

wherein R is a lower alkylene group and A is benzyl with an aliphatic aldehyde.

3. A process substantially as in claim 1 wherein the said aminoalkanol is prepared by reacting a secondary amine of the general formula:

wherein R" is an alkyl group and A is benzyl with a lower alkylene oxide.

4. A process substantially as in claim 1 wherein the said aminoalkanol is prepared by reacting a secondary aminoalkanol having the general formula:

' wherein R is a lower alkylene group and A is a carbobenzoxy group with an aliphatic aldehyde.

5. A process substantially as in claim 1 wherein the said aminoalkanol is prepared by reacting a secondary amine of the general formula:

wherein R" is an alkyl group and A is a carbobenzoxy group with a lower alkylene oxide.

6. A process as in claim 1 for preparing 2-(n-propyl' aminoethyl) 3-amino-4-n-butoxybenzoate hydrochloride which comprises reacting 2-(n-propylamino)ethanol with 3-nitro-4-n-butoxybenzoyl chloride to form 2-(benzyl-npropylamino)ethyl 3-nitro-4-n-butoxybenzoate hydrochloride, subjecting the said 3-nitro-4-n-butoxybenzoate hydrochloride to a hydrogen reducing atmosphere to remove the benzyl group, and thereafter recovering from the reaction mixture 2-(n-propylaminoethyl) 3-amino-4-n-butoxybenzoate hydrochloride uncontaminated by amide products.

7. A process as in claim 1 for preparing Z-(ethylamino)ethyl 3 amino 4 n-butoxybenzoate hydrochloride which comprises reacting 2-(benzylethylamino)ethanol with 3-nitro-4-n-butoxybenzoyl chloride to form 2-(benzylethylamino)ethyl 3-nitro-4-n-butoxybenzoate hydrochloride, subjecting the said 3-nitro-4-n-butoxybenzoatehydrochloride to a hydrogen reducing atmosphere to remove the benzyl group, and thereafter recovering from the reaction mixture 2(ethylamino)ethyl 3-amino-4-nbutoxybenzoate hydrochloride uncontaminated by amide products.

8. A process as in claim 1 for preparing B-(methylamino)-1-propyl 3-amino-4-n-butoxybenzoate hydrochloride which comprises reacting 3-(benzylmethylamino)-1-propanel with 3-nitro-4-'n-butoxyben z oyl chloride to form 3- (benzylmethylamino) 1'- propyl 3-nitro'4-n-butoxybenizoate hydrochloride, subjecting the said 3-nitro-4-n-butoxybenzoate hydrochloride to a hydrogen reducing at- 9. A process as in claim 1 for preparing l-(n-propylamino)-2-propyl 3-amino-4-n-butoxybenzoate dihydrochloride which comprises reacting l-(benzyl-n-propylamino)-2-propano1 with 3-nitro-4-n-butoxybenzoyl chloride to form l-(benzyl-n-propylamino)-2-propyl 3-nitro-4-nbutoxybenzoate hydrochloride, subjecting the said 3-nitro- 4-n-butoxybenzoate hydrochloride to a hydrogen reducing atmosphere to remove the benzyl group, and recovering from the reaction mixture 1-(nrpropy]amino)-2-pr0- pyl 3-amino-4-n-butoxybenzoate dihydrochloride uncontaminated by amide products.

10. A process as in claim 1 for preparing 2-(n-propyl- 12 V 'amino) 1 butyl 3-amino-4-n-butoxybenzoate dihydrofchloride which comprises reacting ,2-(benzyl-n-propyl- 'arnino)-'1 -butanol with 3-nitrov4 n-butoxybenzoyl c1110,- ride to form 2-(benzyl-n-propylamino)-1-butyl 3 nitro-4- n-butoxyb enzoate' hydrochloride, subjecting the said 3- nitro-4-n-butoxybenzoate hydrochloride to a hydrogen reducing atmosphereto remove the benzyl group, and recovering from the reaction mixture.2-(n-propylamino)-1- butyl 3-amino-4-n=butoxybenzoate dihydrochloride un --contaminated by amide products.

References Cited in the file of this patent UNITED STATES PATENTS Great Britain Feb."5, 194i. 

1. A PROCESS OF PREPARING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE GENERAL FORMULA: 